Why Genetic Testing is Crucial
- With advancements in precision medicine, genetic testing and targeted therapies like PARP inhibitors have become integral in prostate cancer management.
- The identification of PGVs in DNA repair genes such as BRCA1, BRCA2, and others is paramount in guiding treatment strategies and family counseling.
Prostate cancer remains a predominant malignancy among men, posing significant treatment challenges, particularly in advanced stages. With advancements in precision medicine, genetic testing and targeted therapies like PARP inhibitors have become integral in prostate cancer management. This article examines the clinical utility of genetic testing, particularly in identifying pathogenic germline variants (PGVs), and the role of PARP inhibitors in enhancing therapeutic outcomes.
“That really starts a whole new discussion of genetic testing and prostate cancer. We know that it is important that our patients with metastatic prostate cancer all have a discussion about hereditary genetic testing. Because a significant subset of men with metastatic prostate cancer are born with a germline genetic predisposition to getting prostate cancer,” Dr. David Wise, medical oncologist, cancer researcher and the director of urologic medical oncology at NYU Langone Cancer Center, tells SurvivorNet.
“And so the reason why we want to find one of those genes is because we can use this class of treatments [PARP inhibitors] to essentially stress that cancer to the point where the cancer is unable to repair its own DNA and that gives us a therapeutic response,” he adds.
Genetic Testing in Prostate Cancer
Genetic testing is crucial for identifying mutations that influence prostate cancer risk, prognosis, and therapeutic response. The identification of PGVs in DNA repair genes such as BRCA1, BRCA2, and others is paramount in guiding treatment strategies and family counseling.
- Prevalence and Significance of PGVs: The identification of PGVs is not only vital for the patient’s treatment but also for familial risk assessment. The PROCLAIM trial revealed that 10% of prostate cancer patients carry a PGV, with 49% showing variants of uncertain significance (VUS). These genetic findings are critical in altering treatment and follow-up plans, with patients harboring PGVs more likely to receive treatment modifications compared to those with negative or VUS results.
- Disparities in Genetic Testing: Despite the known benefits of genetic testing, recent data show that a significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) are not undergoing recommended genetic testing for HRR mutations. A recent study found that only 37.7% of patients with mCRPC received HRR testing, despite the high prevalence of HRR mutations in this population. Disparities in testing were linked to socioeconomic factors, insurance status, and treatment outside academic centers, underscoring the need for improved access to genetic testing in diverse clinical settings.
A significant portion of men with prostate cancer, particularly those with intraductal histology, possess germline mutations that can influence treatment choices and screening for additional cancers. For men with metastatic prostate cancer who haven’t undergone germline genetic testing, it is recommended to consider genetic counseling and testing for specific genes such as MLH1, MSH2, MSH6, PMS2 (for Lynch syndrome), BRCA1, BRCA2, ATM, PALB2, and CHEK2. About 5-10% of patients carry germline mutations in DNA mismatch repair genes, potentially qualifying them for PARP inhibitors.
National Comprehensive Cancer Network (NCCN) Guidelines recommend germline and tumor testing for HRRm in all patients with metastatic prostate cancer and consideration of testing for patients with regional disease.
“I think really any patient with prostate cancer can ask their doctor if they should get germline genetic testing or genetic testing, looking to see if they have an inherited mutation that may have made them more at risk for prostate cancer. That can impact your treatment and it can impact your family and potential screening for cancers for them in the future,” Dr. Hannah McManus, medical oncologist at Duke Cancer Center, told SurvivoNet
Next-generation sequencing of prostate tumor tissue may also be considered to identify somatic genomic alterations that could guide treatment, particularly for refractory cases. This can reveal actionable mutations for which targeted therapies, such as PARP inhibitors, pembrolizumab, or TRK inhibitors, may be available, or for which clinical trials are ongoing. However, these targeted treatments are generally reserved for cases resistant to taxanes and androgen signaling inhibitors, rather than as initial therapy.
For patients with metastatic prostate cancer, genetic testing is essential and results could change the treatment plan.
“For metastatic prostate cancer, it’s pretty straightforward to me,” Dr. Michael Carducci, a medical oncologist at Johns Hopkins Kimmel Cancer Center, told SurvivorNet.
“I think really every patient with metastatic prostate cancer should be having next-generation sequencing to help guide treatment decisions and making sure all medication therapies are being evaluated. Molecular profiling tests for localized prostate cancer are for very specific situations and there is some controversy around when to use them,” he added.
PARP Inhibitors
Genomic testing is recommended for men with advanced prostate cancer who may qualify for molecularly targeted therapies. The American Society of Clinical Oncology (ASCO) has issued a provisional clinical opinion supporting both somatic and germline genomic testing in cases of metastatic or advanced cancer, including prostate cancer, when there are approved genomic biomarker-linked therapies available, such as PARP inhibitors for men with metastatic castration-resistant prostate cancer (mCRPC) and HRR deficiency-related alterations.
Current evidence indicates that PARP inhibitors show the highest response rates in individuals with germline or somatic BRCA1/2 mutations. However, the benefits of PARP inhibitor therapy may vary across different subgroups with BRCA1/2 alterations. Specifically, due to the relatively rare occurrence of BRCA1 mutations compared to BRCA2 mutations in prostate cancer, the effectiveness of PARP inhibitors in the BRCA1 subset is still unclear and will be better understood with more data.
Beyond BRCA1 and BRCA2, both preclinical and clinical studies suggest that pathogenic or likely pathogenic variants in other genes associated with the HRR pathway may also influence sensitivity to PARP inhibitors. In prostate cancer, these genes include:
- ATM
- CHEK2
- PALB2
- FANCA
- RAD51B/C/D
- BRIP1
Treatment for CRPC with HRR Deficiency
Several PARP inhibitors have been approved for the treatment of men with CRPC who have alterations linked to HRR deficiency. However, the approvals for rucaparib (brand name Rubraca) and niraparib/abiraterone acetate (brand name Akeega) are specifically limited to those with pathogenic variants in BRCA1 or BRCA2. In contrast, olaparib (brand name Lynparza), either alone or combined with abiraterone acetate, and talazoparib/enzalutamide (brand name Talzenna and Xtandi) are approved for use in patients with alterations in several genes, some of which have not been individually proven to predict responsiveness to PARP inhibition. Among all HRR genes involved in DNA damage response pathways, BRCA2 variants seem to derive the most significant benefit from PARP inhibitors.
There has been no direct comparison between these agents, so the choice of treatment depends on patient-specific factors such as mutational status, prior therapies, comorbidities, and the expected side effect profiles.
